Muscle regeneration is sustained by infiltrating macrophages and consequent satellite cell (SC) activation 1 – 4 . Macrophages and SC communicate in different ways 1 – 5 but their metabolic interplay was never investigated so far. Here, we found that muscle injuries and aging are characterized by intratissutal glutamine restriction. Low glutamine levels endow macrophages with the metabolic ability to secrete glutamine via enhanced glutamine synthetase (GS) activity at the expense of glutamate dehydrogenase-1 (GLUD1)-mediated glutamine oxidation. Glud1 knockout (KO) macrophages display constitutively high GS activity which prevents glutamine shortage. Import of macrophage-derived glutamine by SC through the glutamine-transporter SLC1A5 activates mTOR and promotes SC proliferation and differentiation. Consequently, macrophage-specific deletion or pharmacological inhibition of GLUD1 improves muscle regeneration and functional recovery in response to acute injury, ischemia, or aging. Conversely, SLC1A5 blockade in SC or GS inactivation in macrophages negatively affects SC functions and muscle regeneration. These results highlight a metabolic cross-talk between SC and macrophages whereby macrophage-derived glutamine sustains SC functions. Thus, GLUD1 targeting offers new therapeutic opportunities for the regeneration of injured or aged muscles.

Two different structures of zeolites, faujasite (FAU) and Linde type A (LTA), were studied to investigate their suitability for drug delivery systems (DDS). The zeolites in the sodium form (NaY and NaA) were used as hosts for encapsulation of α-cyano-4hydroxycinnamic acid (CHC). CHC, an experimental anticancer drug, was encapsulated in both zeolites by diffusion in liquid phase. These new drug delivery systems, CHC@zeolite, were characterized by spectroscopic techniques (FTIR, 1 H NMR, 13 C and 27 Al solidstate MAS NMR, and UV−vis), chemical analysis, powder X-ray diffraction (XRD) and scanning electron microscopy (SEM). The effect of the zeolites and CHC@zeolite drug deliveries on HCT-15 human colon carcinoma cell line viability was evaluated. Both zeolites alone revealed no toxicity to HCT-15 cancer cells. Importantly, CHC@zeolite exhibit an inhibition of cell viability up to 585-fold, when compared to the non-encapsulated drug. These results indicate the potential of the zeolites for drug loading and delivery into cancer cells to induce cell death. 50 previously reported the preparation of a DDS based in zeolite Y 51 with an anticancer drug and demonstrated its efficacy against 52 colorectal carcinoma (CRC) cells in vitro. 22 CRC is the most 53 common type of tumor in Western countries, being men 54 slightly more often affected. 23 Treatment of CRC includes 55 surgery, radiotherapy, and/or chemotherapy. However, the 56 treatment design depends largely on the cancer stage. Despite 57 the progress made with the introduction of new cytotoxic 58 agents 24−28 and medical practices, survival rates of patients with 59 CRC changed little over the last 20 years, 29 justifying the need 60 for more effective therapies and new drugs. 61 α-Cyano-4-hydroxycinnamic acid (CHC) is a compound 62 derived from cinnamic acid and is a competitive inhibitor of 63 monocarboxylate transporter 1 (MCT1), 30 a protein recently 64 shown to be upregulated in colorectal and other cancers and 65 thus a potential target for cancer therapy. 31−33 Published data 66 demonstrated the cytotoxic and cytostatic effectiveness of 67 CHC, 34,35 both in vitro and in vivo. 36,37 CHC used here in a 68 model of colon carcinoma was chosen as a guest in two 69 different structures of zeolites for drug delivery. Due to their 70 structural properties, zeolites have attracted much research

The studies of potentiation of 5-fluorouracil (5-FU), a traditional drug used in the treatment of several cancers, including colorectal (CRC), were carried out with zeolites Faujasite in the sodium form, with different particle sizes (NaY, 700nm and nanoNaY, 150nm) and Linde type L in the potassium form (LTL) with a particle size of 80nm. 5-FU was loaded into zeolites by liquid-phase adsorption. Characterization by spectroscopic techniques (FTIR, (1)H NMR and (13)C and (27)Al solid-state MAS NMR), chemical analysis, thermal analysis (TGA), nitrogen adsorption isotherms and scanning electron microscopy (SEM), demonstrated the successful loading of 5-FU into the zeolite hosts. In vitro drug release studies (PBS buffer pH 7.4, 37°C) revealed the release of 80-90% of 5-FU in the first 10min. To ascertain the drug release kinetics, the release profiles were fitted to zero-order, first-order, Higuchi, Hixson-Crowell, Korsmeyer-Peppas and Weibull kinetic models. The in vitro dissolution from the drug delivery systems (DDS) was explained by the Weibull model. The DDS efficacy was evaluated using two human colorectal carcinoma cell lines, HCT-15 and RKO. Unloaded zeolites presented no toxicity to both cancer cells, while all DDS allowed an important potentiation of the 5-FU effect on the cell viability. Immunofluorescence studies provided evidence for zeolite-cell internalization.

BackgroundColorectal cancer (CRC) is one of the most common malignancies and a leading cause of cancer death worldwide. Most cancer cells display high rates of glycolysis with production of lactic acid, which is then exported to the microenvironment by monocarboxylate transporters (MCTs). The main aim of this study was to evaluate the significance of MCT expression in a comprehensive series of primary CRC cases, lymph node and hepatic metastasis.MethodsExpressions of MCT1, MCT4, CD147 and GLUT1 were studied in human samples of CRC, lymph node and hepatic metastasis, by immunohistochemistry.ResultsAll proteins were overexpressed in primary CRC, lymph node and hepatic metastasis, when compared with non-neoplastic tissue, with exception of MCT1 in lymph node and hepatic metastasis. MCT1 and MCT4 expressions were associated with CD147 and GLUT1 in primary CRC. These markers were associated with clinical pathological features, reflecting the putative role of these metabolism-related proteins in the CRC setting.ConclusionThese findings provide additional evidence for the pivotal role of MCTs in CRC maintenance and progression, and support the use of MCTs as biomarkers and potential therapeutic targets in primary and metastatic CRC.